The central theme of this PPG is to identify novel signaling molecules and pathways that contribute to the pathogenesis of heart failure (HF) after cardiac injury and also to study potential intersecting signaling and cellular mechanisms for repair of failing myocardium. The proposal specifically will identify critical molecular mechanisms that cause the cardiac injury that leads to HF and determine cellular and molecular mechanisms that promote repair of the damaged heart. The latter will involve novel pathways involved in the generation of new myocytes. The unifying theme and ultimate goal of our group's application is that identification of molecular and cellular pathways involved in either cardiac injury or repair will lead to novel translational studies with a shared PPG vision towards identifying new therapeutic strategies for reversing HF and improving outcomes, which is something desperately needed as the incidence of this devastating disease continues to rise. Our efforts will come from multiple but complimentary directions and all investigators will use newly developed mouse models to test individual project hypotheses all focused on the theme of novel mechanisms of cardiac injury and repair. This focused PPG is being led by project leaders who are distinguished scientists in the HF arena with a long history of productivity, and who have recently been brought together in the city of Philadelphia. This has led to natural collaborations that now form the basis for putting together four integrative projects around our central theme that is particularly suited for a PPG application. The themes of each project are: Project 1 (Koch) will study how the novel nuclear activity of G protein-coupled receptor kinase-5 (GRK5) alters myocardial responses to stressors that cause hypertrophy, injury and eventually lead to HF;Project 2 (Feldman) will investigate the role of specific adenosine receptor subtypes in cardiac injury induction and protection including the study of novel mechanistic involvement of G protein signaling and calcium (Ca2+);Project 3 (Houser) will study the links between Ca2+ entry through the L-type Ca2+ channel, Ca2+ overload of the sarcoplasmic reticulum (SR), myocyte death from apoptosis and necrosis and HF. These studies will employ a novel mouse model in which Ca2+ influx can be altered. This study will also determine if myocyte death induced by excess Ca2+ influx induces an increase in stem cell derived new myocyte formation to regenerate cardiac tissue;and Project 4 (Force) involves determining mechanistically how tyrosine kinase inhibitors used as cancer therapeutics cause a novel reversible cardiomyopathy that may involve alterations in cellular energetics as well as a loss of the heart's repair and regenerative properties. Importantly, all Project leaders have expertise in translating their basic results, which represents a real strength of our program.